Myasthenia Gravis

Surya Cahyadi Junus

Outline
Background
Anatomy
Pathophysiology
Clinical Presentation
Work-up
Treatment
Rehabilitation
Background
Acquired autoimmune disorder
Clinically characterized by:
Weakness of skeletal muscles
Fatigability on exertion.
First clinical description in 1672 by Thomas
Willis
Myasthenia Gravis
Clinical Classification

I. Ocular alone
IIa. Mild generalized
IIb. Moderately severe generalized plus
usually some bulbar involvement
III. Acute severe over weeks-months with
severe bulbar involvement
IV. Late severe with marked bulbar
involvement
Anatomy
Neuromuscular Junction (NMJ)
Components:
Presynaptic membrane
Postsynaptic membrane
Synaptic cleft
Presynaptic membrane contains vesicles with
Acetylcholine (ACh) which are released into
synaptic cleft in a calcium dependent manner
ACh attaches to ACh receptors (AChR) on
postsynaptic membrane
Anatomy
Neuromuscular Junction (NMJ)
The Acetylcholine receptor (AChR) is a sodium
channel that opens when bound by ACh
There is a partial depolarization of the postsynaptic
membrane and this causes an excitatory postsynaptic
potential (EPSP)
If enough sodium channels open and a threshold
potential is reached, a muscle action potential is
generated in the postsynaptic membrane
Pathophysiology
In MG, antibodies are directed toward the
acetylcholine receptor at the neuromuscular
junction of skeletal muscles
Results in:
Decreased number of nicotinic acetylcholine
receptors at the motor end-plate
Reduced postsynaptic membrane folds
Widened synaptic cleft
Pathophysiology
T-cell mediated immunity has some influence
Thymic hyperplasia and thymomas are
recognized in myasthenic patients*
Clinical Presentation
Fluctuating weakness increased by exertion
Weakness increases during the day and improves
with rest
Extraocular muscle weakness
Ptosis is present initially in 50% of patients and
during the course of disease in 90% of patients
Head extension and flexion weakness
Weakness may be worse in proximal muscles
Clinical presentation
Progression of disease
Mild to more severe over weeks to months
Usually spreads from ocular to facial to bulbar to truncal
and limb muscles
Often, symptoms may remain limited to EOM and eyelid
muscles for years
Remissions
Spontaneous remissions rare
Most remissions with treatment occur within the first three
years
Clinical presentation
Basic physical exam findings
Muscle strength testing
Recognize patients who may develop respiratory
failure (i.e. difficult breathing)
Sensory examination usually normal
Clinical presentation
Muscle strength
Facial muscle weakness
Bulbar muscle weakness
Limb muscle weakness
Respiratory weakness
Ocular muscle weakness
Clinical presentation
Facial muscle weakness is almost
always present
Ptosis and bilateral facial muscle
weakness
Sclera below limbus may be exposed due
to weak lower lids
Clinical presentation
Occular muscle weakness
Asymmetric
Usually affects more than one extraocular muscle and
is not limited to muscles innervated by one cranial
nerve
Weakness of lateral and medial rectus
Ptosis caused by eyelid weakness
Diplopia is very common
Clinical presentation
Bulbar muscle weakness
Palatal muscles
Nasal voice, nasal regurgitation
Chewing may become difficult
Severe jaw weakness may cause jaw to hang open
Swallowing may be difficult and aspiration may
occur with fluidscoughing and choking while
drinking
Neck muscles
Neck flexors affected more than extensors
Clinical presentation
Limb muscle weakness
Upper limbs more common than lower limbs

Upper Extremities Lower Extremities

Deltoids Hip flexors (most common)
Wrist extensors Quadriceps
Finger extensors Hamstrings
Triceps > Biceps Foot dorsiflexors
Plantar flexors
Clinical presentation
Respiratory muscle weakness
Weakness of the intercostal muscles and the diaghram
may result in CO2 retention due to hypoventilation
May cause a neuromuscular emergency

Weakness of pharyngeal muscles may collapse the upper

airway
Monitor negative inspiratory force, vital capacity and tidal
volume
Do NOT rely on pulse oximetry
Arterial blood oxygenation may be normal while CO2 is retained
Differentials Diagnosis
Basilar Artery Multiple Sclerosis
Thrombosis Neuropathy
Brainstem gliomas Botulism
Lambert-Eaton Oculopharyngeal
Myasthenic Syndrome muscular dystrophy
Work-up
Lab studies
Anti-acetylcholine receptor antibody
Positive in 74%
80% in generalized myasthenia
50% of patients with pure ocular myasthenia
Anti-striated muscle antibody
Present in 84% of patients with thymoma who are
younger than 40 years
It is useful as a screening test for MG in older patients,
especially when tests for muscle AChR antibodies are
negative.
Work-up
Imaging studies
Chest x-ray
Plain anteroposterior and lateral views may identify a
thymoma as an anterior mediastinal mass
Chest CT scan is mandatory to identify thymoma
MRI of the brain and orbits may help to rule out
other causes of cranial nerve deficits but should
not be used routinely
Work-up
Electrodiagnostic studies
Repetitive nerve stimulation
Electrodiagnostic studies:
Repetitive Nerve Stimulation

Low frequency RNS (1-5Hz)

Locally available Ach becomes depleted at all
NMJs and less available for immediate release
Results in smaller EPSPs
Repetitive nerve stimulation
Most common employed stimulation rate is
3Hz
Several factors can afect RNS results
Lower temperature increases the amplitude of the
compound muscle action potential
Many patients report clinically significant improvement
in cold temperatures
AChE inhibitors prior to testing may mask the
abnormalities and should be avoided for at least 1
day prior to testing
Workup
Pharmacological testing
Edrophonium (Tensilon test)
Patients with MG have low numbers of AChR at
the NMJ
Ach released from the motor nerve terminal is
metabolized by Acetylcholine esterase
Edrophonium is a short acting Acetylcholine
Esterase Inhibitor that improves muscle
weakness (reversible acetylcholinesterase
inhibitor.)
Evaluate weakness (i.e. ptosis and
opthalmoplegia) before and after administration
 Edrophonium (by the so-called Tensilon test)
is used to differentiate myasthenia
gravis from cholinergic crisis
In a cholinergic crisis, where a person has
too much neuromuscular stimulation,
edrophonium will make the muscle weakness
worse by inducing a depolarizing block.
CHOLINERGIC CRISIS
Sweating, bronchospasm with wheeze,
cyanosis, colic, confusion, fasciculation, ataxia,
small pupils, bradycardia, hypertension,
seizures.
The SLUDGE syndrome (i.e., salivation,
lacrimation, urinary incontinence, diarrhoea, GI
upset and hyper motility, and emesis)
As a result of cholinergic crisis, the muscles stop
responding to the bombardment of ACh, leading
to flaccid paralysis, respiratory failure
Workup
Pharmacological testing
Edrophonium (Tensilon test)
Differentiate a myasthenic crisis from a
cholinergic crisis.
A positive test is judged by improvement of
weakness in 3 minutes of the injection.
Steps

0.1ml of a 10 mg/ml edrophonium solution is

administered as a test
TENSILON TEST
Workup
Pharmacological testing

Before After
Treatment
AChE inhibitors
Immunomodulating therapies
Plasmapheresis
Thymectomy
Important in treatment, especially if thymoma is
present
Treatment
AChE inhibitor
Pyridostigmine bromide (Mestinon)
Starts working in 30-60 minutes and lasts 3-6 hours
Individualize dose
Adult dose:
60-960mg/d PO
2mg IV/IM q2-3h
Caution
Check for cholinergic crisis
Others: Neostigmine Bromide (Prostigmin)
The drug blocks the active site of
acetylcholinesterase Enzyme can no longer
break down the acetylcholine molecules before
they reach the postsynaptic membrane receptors.
Treatment
Immunomodulating therapies
Prednisone
Most commonly used corticosteroid in US
Significant improvement is often seen after a
decreased antibody titer which is usually 1-4 months
Intravenous immunoglobulin

IVIg seems to affect immune homeostasis by

interfering at multiple levels. The mode of action
most directly related to is likely the modulation of
the pathogenic autoantibody response.
Suppressing or modifying the autoimmune
pathogenic mechanisms of myasthenia gravis.
The procedure usually entails the administration
of 0.4 g/ kg body weight human pooled IgG over
3 to 5 days,
Treatment
Behavioral modifications
Diet
Patients may experience difficulty chewing and
swallowing due to oropharyngeal weakness
If dysphagia develops, liquids should be thickened
Thickened liquids decrease risk for aspiration
Activity
Patients should be advised to be as active as
possible but should rest frequently and avoid
sustained activity
Educate patients about fluctuating nature of
weakness and exercise induced fatigability
Complications of MG
Respiratory failure
Dysphagia
Complications secondary to drug treatment
Long term steroid use
Osteoporosis, cataracts, hyperglycemia, HTN
Gastritis, peptic ulcer disease
Pneumocystis carinii
Prognosis
Untreated MG carries a mortality rate of 25-
31%
Treated MG has a 4% mortalitiy rate
40% have ONLY occular symptoms
Only 16% of those with occular symptoms at
onset remain exclusively occular at the end of 2
years
Rehabilitation
Strategies emphasize
Patient education
Providing adaptive equipment
Providing assistive devices
Exercise is not useful
 Thank you!
Questions, comments, or suggestions?